GARFT is a folate-dependent enzyme in the de novo purine biosynthesis pathway. This pathway is critical to cell division and proliferation. Shutting down this pathway is known to have an antiproliferative effect, in particular, an antitumor effect. Compounds that inhibit GARFT consequently inhibit the growth and proliferation of the cells of higher organisms or microorganisms such as bacteria, yeast and fungi.
A number of folate analogs have been synthesized and studied for their ability to inhibit GARFT. A prototypical specific tight-binding inhibitor of GARFT, 5,10-dideazatetrahydrofolic acid, has been reported to show antitumor activity. See F. M. Muggia, "Folate antimetabolites inhibitor to de novo purine synthesis," New Drugs, Concepts and Results in Cancer Chemotherapy, Kluwer Academic Publishers, Boston (1992), 65-87.
Antifolates or antifoles are a subclass of antiproliferative antimetabolites and are antagonists of the vitamin folic acid. Typically, antifolates closely resemble the structure of folic acid and incorporate the characteristic P-benzoyl glutamate moiety of folic acid. The glutamate moiety of folic acid takes on a double negative charge at physiological pH. Thus, this compound and its analogs have an active energy-driven transport system to cross the cell membrane and exert a metabolic effect.
Compounds useful as antiproliferative agents or GARFT inhibitors, such as certain glutamic acid derivatives, have been recently developed as described in U.S. application Ser. No. 08/282,293 to Varney et al., filed Jul. 28, 1994, and in International Application PCT/US94/00418 to Varney et al., filed on Jan. 18, 1994, the disclosures of which are herein incorporated by reference. Such compounds also have antitumor, antiinflammatory, antipsoriatic and/or immunosuppressive activity. The present invention relates to advantageous methods of making such compounds in optically pure forms in good yields. The invention also relates to optically pure intermediates useful for making the antiproliferative agents/GARFT inhibitors and to methods of making these intermediates.